A Modified Peptide Derived from Goodpasture Autoantigen Arrested and Attenuated Kidney Injuries in a Rat Model of Anti-GBM Glomerulonephritis.

Abstract

In Goodpasture disease, the noncollagenous domain 1 of the <i>α</i>3 chain (<i>α</i>3NC1) of type IV collagen is the main target antigen of antibodies against glomerular basement membrane (GBM). We previously identified a nephritogenic epitope, P14 (<i>α</i>3_127-148), that could induce crescentic nephritis in WKY rats, and defined its core motif. Designing a modified peptide, replacing critical pathogenic residues with nonpathogenic ones (on the basis of homologous regions in <i>α</i>1NC1 chain of type IV collagen, known to be nonpathogenic), might provide a therapeutic option for anti-GBM GN. We synthesized a modified peptide, replacing a single amino acid, and injected it into <i>α</i>3-P14-immunized rats from day 0 (the early-treatment group) or a later-treatment group (from days 17 to 21). A scrambled peptide administrated with the same protocol served as a control. The modified peptide, but not the scrambled peptide, attenuated anti-GBM GN in both treatment groups, and halted further crescent formation even after disease onset. Kidneys from the modified peptide-treated rats exhibited reductions in IgG deposits, complement activation, and infiltration by T cells and macrophages. Treatment also resulted in an anti-inflammatory cytokine profile versus a proinflammatory profile for animals not receiving the modified peptide; it also reduced <i>α</i>3-P14-specific T cell activation, modulated T cell differentiation by decreasing Th17 cells and enhancing the ratio of Treg/Th17 cells, and inhibited binding of <i>α</i>3-P14 to antibodies and MHC II molecules. A modified peptide involving alteration of a critical motif in a nephritogenic T cell epitope alleviated anti-GBM GN in a rat model. Our findings may provide insights into an immunotherapeutic approach for autoimmune kidney disorders such as Goodpasture disease.